Hindawi Publishing Corporation

Autoimmune Diseases
Volume 2012, Article ID 645967, 11 pages
doi:10.1155/2012/645967

Review Article
Neurological Disorders in Primary Sjogrens Syndrome
1 Jacques-Olivier Pers,1, 2 Valerie Devauchelle-Pensec,1 and Pierre Youinou1
Gabriel J. Tobon,
1 EA

Immunologie et Pathologie, Universite de Bretagne Occidentale et Centre Hospitalier Universitaire de Brest,

BP 824, F2969 Brest, France
2 Laboratory of Immunology, Brest University Medical School, BP 824, 2969 Brest, France
Correspondence should be addressed to Jacques-Olivier Pers, jacques-olivier.pers@univ-brest.fr
Received 11 October 2011; Accepted 15 December 2011
Academic Editor: Jozelio Freire de Carvalho
et al. This is an open access article distributed under the Creative Commons Attribution
Copyright 2012 Gabriel J. Tobon
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Sjogrens syndrome is an autoimmune disease characterized by an autoimmune exocrinopathy involving mainly salivary and
lacrimal glands. The histopathological hallmark is periductal lymphocytic infiltration of the exocrine glands, resulting in loss of
their secretory function. Several systemic manifestations may be found in patients with Sjogrens syndrome including neurological
disorders. Neurological involvement ranges from 0 to 70% among various series and may present with central nervous system
and/or peripheral nervous system involvement. This paper endeavors to review the main clinical neurological manifestations in
Sjogren syndrome, the physiopathology, and their therapeutic response.

1. Epidemiology of Neurological Involvement in

Sjogrens Syndrome
Sjogrens syndrome (SS) is a common autoimmune disease (AID) characterized by an autoimmune exocrinopathy
[1] involving mainly salivary and lacrimal glands. The
histopathological hallmark is periductal lymphocityc infiltration of the exocrine glands, resulting in loss of their
secretory function. This disease occurs alone as primary
SS (pSS), or in a background of connective tissue diseases
as secondary SS (sSS). Even though keratoconjunctivitis
sicca (resulting from the involvement of lacrimal glands)
and xerostomia (resulting from that of salivary glands) are
usually prominent, SS presents as a multifaceted condition
with a broad variety of clinical manifestations (i.e., fatigue,
arthralgias, Raynauds phenomenon, interstitial pneumonias, lymphadenopathy, vasculitic urticaria, purpura, renal
tubular acidosis, and neurological involvement) and biological abnormalities of B lymphocytes manifests as hypergammaglobulinemia; production of anti-SSA and anti-SSB
autoantibodies and of rheumatoid factor; and an increased
risk of non-Hodgkins B-cell lymphoma (NHL) [2, 3].
This polymorphism accounts for the delay in the diagnosis. As a consequence, there is very likelihood that the
prevalence of the disease is far higher than previously

estimated [4]. European Community Study Group on diagnostic criteria for SS (2002) is used to classify patients with
the disease [5].
Neurological involvement in SS may be manifested in
the central nervous system (CNS) and/or peripheral nervous
system (PNS). The prevalence of neurological manifestations
ranges between 0 and 70% according to the investigators
and depending on the recruitments of their clinics, but in
general, such complications occur in about 20% of patients
[612]. This impressive heterogeneity may be explained
by the medical department where patients are recruited
(i.e., internal medicine versus neurology) [8], the diagnosis
criteria for pSS used (before 2002), or the definition of
specific neuropathies and the diagnostic test performed to
classify the neurological involvement (mainly in asymptomatic patients). Notably, series published before year 2002
included some patients as considered as suering from pSS
without histology and/or antibody evidence. Comparison
between these series is impeded by the heterogeneity in the
diagnostic criteria.
To illustrate this concern, in a series by Lafitte et al.
[8], neurological manifestations in pSS were analyzed in
two cohorts from two medical departments (25 patients
from internal medicine and 11 patients from neurology
department). Neurological involvement was found in 40%

2
of patients from the internal medicine department. PNS
involvement was present in 4 of 25 patients from the internal
medicine group, whereas, in the neurology department,
there were 10 of 11 patients (mainly axonal sensorimotor/sensory polyneuropathy). CNS involvement occurred in
7/25 patients from the internal medicine department and
4/11 from neurology. Cognitive dysfunction was the most
frequent CNS finding. Thus, these results confirmed that
neurological involvement in SS varies according to medical
department where patients are evaluated.
Selection of patients in the dierent series is other matter
of concern. Most of these series have been constructed retrospectively. For example, Mori et al. [11] reported 92 patients
evaluated by neurological symptoms, but the majority of
patients (93%) were diagnosed with pSS after neuropathy.
Patients were evaluated between 1985 and 2004. Thus, part
of patients was diagnosed with the criteria proposed by the
Diagnostic Committee of Health and Welfare of Japan (1999)
[13]. On the other hand, Gransson et al. [12] in a crosssectional study evaluated PNS in 62 pSS patients applying the
American-European classification criteria. In this series, 27%
of patients presented neuropathy after clinical examination,
and 55% had abnormal conduction studies.
Neurological manifestations may precede the sicca symptoms in 40 to 93% of the cases [8, 14]. As described by
Mori et al. [11], 93% of patients were diagnosed with pSS
after neuropathy symptoms appeared. Patients with pSS and
neurological involvement are older than patients without
neurological implication [9, 10].
pSS-associated neurological main manifestations are
listed in Table 1. PNS involvement in pSS is well characterized, manifested mainly as axonal polyneuropathies (sensory
and sensorimotor), trigeminal neuropathy, and small-fiber
neuropathy. Distal axonal sensory or sensorimotor polyneuropathy accounts for over 50% of cases of PNS involvement
[6, 7, 15]. On the other hand, CNS manifestations are
heterogeneous, manifested as focal or diuse involvement.
Most series reported that PNS involvement is more common
than CNS disease. However, Delalande et al. reported the
same frequency of central and peripheral nervous system
involvements [15].
Other aspect to analyze is the severity of evaluated
patients. Most of the previous studies have been conducted at
reference centers, thus probably patients seen in these studies
have a more severe disease. Lopate et al. [16] showed the
prevalence of neuropathy in pSS in an outpatient setting. In
the outpatient context, they evaluated 22 pSS patients and
10 controls for evidence of neuropathy. Isolated small-fiber
neuropathy was found in 45% of cases and none of controls. Large-fiber dysfunction was similar between the two
groups. This study highlights the importance of subclinical
neuropathy present in many pSS patients that may lead to
disability related to painful distal paresthesias and also the
clinical dierences according to the patient setting.

2. Pathophysiology
The pathogenic mechanisms responsible for most forms of
neurological involvement in pSS are unknown. To explain

Autoimmune Diseases
Table 1: Neurological manifestations in primary Sjogrens syndrome.
Peripheral disorders

Axonal polyneuropathies
(i) Symmetric pure sensory
peripheral neuropathy
(ii) Symmetric sensorimotor
peripheral neuropathy

Sensory ganglioneuronopathy

Motor neuropathy

Small-fiber neuropathy
Multiple mononeuritis

Central disorders
Focal
(i) Seizures
(ii) Movement disorders
(iii) Cerebellar syndrome
(iv) Optic neuropathies
(v) Pseudotumor lesions
(vi) Motor and sensory
loss
Multifocal disease
(i) Cognitive impairment
(ii) Encephalopathy
(iii) Dementia
(iv) Psychiatric
abnormalities
(v) Aseptic
meningoencephalitis
Spinal cord dysfunction
(i) Chronic progressive
myelopathy
(ii) Lower motor neuron
disease
(iii) Neurogenic bladder
(iv) Acute transverse
myelitis
Progressive-multiple
sclerosis-like syndrome
Central nervous system
vasculitic involvement

Trigeminal and other cranial

nerves neuropathies
Autonomic neuropathies
Demyelinating
polyradiculoneuropathy

this involvement, many hypothesis have been considered.

Three pathogenic factors may explain the CNS disorders.
The first hypothesis is the direct infiltration of the CNS by
mononuclear cells [17]. Bakchin et al. [17] reported a patient
with ataxia, oculomotor paralysis, seizures, and a large lymphocytic infiltrate at postmortem examination. The second
hypothesis is the vascular involvement. The vascular injury
may be related to the presence of antineuronal antibodies and
anti-Ro antibodies [18]. Finally, Alexander [1921] suggest
that the underlying mechanism of CNS lesion in pSS is the
ischemia secondary to small vessel vasculitis.
Several mechanisms are suggested for the development of
the involvement of PNS in pSS patients. Vascular or peripheral inflammatory infiltrates with or without necrosis may be
found [14, 22]. Vasculitis of the vasa nervorum has also been
proposed as pathogenic mechanism in PNS involvement
[14]. However, others studies have not replicated these findings [15, 23]. In the case of motor neuropathy, necrotizing

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3
these manifestations in pSS are a fortuity association and
the link between CNS manifestations and pSS is not well
characterized.

CNS

Infiltration by
mononuclear
cells

Vascular involvement

Ischemia secondary to vessel vasculitis

Antibodies role?

PNS

Infiltration by

Vascular

mononuclear cells:
ganglionitis

Vasculitis vasa nervorum

Necrotizing vasculitis
Antibodies role?

Figure 1: Pathophysiological mechanism implicated in the development of central and peripheral nervous system manifestations in
primary Sjogrens syndrome.

vasculitis may be found. Lymphocytic infiltration of the

dorsal ganglia has been found in some cases of sensory
neuronopathy [24]. Antineuronal antibodies have also been
described in patients with PNS involvement [25], but the
pathological role of these antibodies remains unknown.
Antibodies against the type 3 muscarinic receptor have also
been described in pSS. These antibodies have shown to be
functional, and they are able to inhibit neuron-mediated
contraction throughout the gastrointestinal tract. Thus,
these antibodies may eventually explain part of the broader
autonomic dysfunction found in pSS patients [26]. Figure 1
summarizes the main pathophysiological mechanisms.

3. Central Nervous System Involvement

CNS involvement has not been as well defined as the PNS
involvement. Thus, CNS involvement in pSS is controversial,
and its prevalence ranges from 0% to 68% [15], according
to dierent series [2729]. Garca-Carrasco et al. reported
only 1% of CNS involvement (4 patients in a cohort of
400 pSS patients) [29]. SNC involvement varies from diuse
compromise, manifested as cognitive deficits or meningoencephalitis, to focalized compromise, with spinal involvement
or optic myelitis. The diagnostic is more dicult compared
to PNS involvement, due to unspecific symptoms.
Alexander et al. [18] described CNS manifestations in
20% of pSS patients. The same group [6] showed that
63% of patients presenting CNS involvement had PNS
manifestations. Escudero et al. [30] reported that headache is
the main CNS complication in pSS. In addition, subclinical
tissue injury may be determined by magnetic resonance
imaging (MRI). This method also permits to determine the
extension and severity of CNS involvement [27, 31].
Due to high variation in clinical symptoms and signs
derived from CNS involvement, some authors propose that

3.1. Focal Involvement. Focal encephalic involvement is the

main CNS manifestation in pSS [6, 15]. These focal disorders
can include motor and sensory loss with hemiparesis, aphasia, dysarthria, seizures, movement disorders, and cerebellar
syndrome. Their onset may be acute of insidious or even in a
recurring pattern that resembles to multiple sclerosis. Some
criteria such as older age, PNS or cranial nerve involvement,
spinal cord MRI lesions spanning multiple segments, and
cerebral MRI showed cortical brain lesions are characteristic
of pSS involvement and rarely seen in multiple sclerosis
[27, 28].
Spine cord disorders can include acute or chronic
progressive myelopathies, lower motor neuron disease, or
neurogenic bladder [15, 32, 33]. Spine complications may
be associated with encephalic involvement. In the series
by Lafitte et al. [8], myelopathies are reported in 3 of 11
patients with SNC involvement. The clinical picture is often
characterized by transverse myelitis [3234]. Although rare
in pSS, acute and chronic myelopathies are frequently severe
and life-threatening. These manifestations usually respond
poorly to treatment with corticosteroids. Immunosuppressive treatment with cyclophosphamide and steroids has
shown some ecacy in patients with progressive disease (see
Section 7).
Subacute transverse myelitis with high signal on T2
weighted images and abnormal cerebrospinal fluid (CSF)
study (increased protein level and cell count) is a rare but
well-described complication in pSS patients [35, 36].
Optic neuropathies have been also described in pSS [37].
This manifestation can be asymptomatic. Alexander [38]
reported seven cases of retrobulbar optic neuropathy in pSS
patients. Four asymptomatic patients were diagnosed by
visual evoked potentials.
Sanahuja et al. [31] described a case of a pSS patient
with a large tumefactive brain lesion, who responded well
to oral corticosteroid treatment. This lesion, although rarely
reported, has to be considered in pSS patients. Dierential
diagnosis includes lymphoma, glioma, abscesses, metastasis,
progressive multifocal leukoencephalopathy, and disseminated encephalomyelitis.
3.2. Diuse Involvement. CNS involvement can be diuse,
presenting encephalopathy, cognitive disfunction, dementia,
psychiatric abnormalities, and aseptic meningoencephalitis
[3941]. This last complication is characterized by abnormal
CSF, with lymphocytic cells and proteins.
Cognitive disturbances of variable severity have been
described in pSS patients without mood disorders [8].
Lafitte el al. reported 8 from 36 pSS patients with cognitive
dysfunction, characterized by frontal executive dysfunction,
impairment in attention control, intellectual decline, and
deterioration of instrumental abilities. Cognitive impartment is not correlated with CSF abnormalities or MRI
findings [42, 43]. Malinow et al. [44] described 25 psychiatric

4
abnormalities in 40 pSS patients. Of 16 patients undergoing
cognitive function testing, 7 presented mild memory impairment with attention and concentration deficits. Belin et al.
[45] evaluated 14 pSS patients with brain MRI, brain 99 m
Tc-SPECT, and neuropsychological testing. In this series, all
patients presented neuropsychological abnormalities, mostly
frontal lobe syndrome and memory problems. The neurological involvement was associated with SPECT abnormalities,
but not MRI imaging results. Ferreiro et al. reported a
patient with diuse angiographic changes, supporting that
an ischemic mechanism caused by CNS vasculitis may be
responsible for the clinical presentation in some patients
[46].
In conclusion, these studies show the wide range of CNS
manifestations that could be associated with pSS. Also, it
is important to recognize cognitive problems, which are
common in pSS, and cognitive evaluation is a sensible tool
sensible to diagnose CNS compromise.

4. Peripheral Nervous System Involvement

As described in epidemiology section, peripheral neuropathy
is the most common neurological complication of pSS. It can
be present between 20 and 50% of patients when subclinical
neuropathy is revealed by a systematic electrophysiological
study [47] and clinically from 10 to 32% [6, 14]. In 1962,
Kaltreider and Talal [22], described for the first time, the
prevalence of neurological involvement in pSS. In this series,
8.3% (n = 9) of 109 patients presented neuropathies.
PNS disease includes axonal polyneuropathies (distal axonal sensory and sensorimotor), neuronopathies,
mononeuropathies, cranial nerves involvement (mainly
trigeminal neuropathy), and autonomic system involvement
(Table 1). Axonal polyneuropathies are the most common
manifestations of PNS involvement found in 50% of PNS
cases [14, 15].
In the series by Gransson et al. [12], 27% of patients
presented peripheral neuropathy and nerve conduction
studies were indicative of motor neuropathy in 31% of cases.
4.1. Axonal Polyneuropathies. The axonal polyneuropathies
are the most frequent clinical presentation of PNS involvement in pSS. It includes distal sensorimotor and sensory
polyneuropathies. Clinical manifestations usually start with
distal and symmetric sensitive involvement. Large-fiber sensory dysfunction is evidenced by electrodiagnostic studies.
4.1.1. Sensory Polyneuropathy. Distal sensory polyneuropathy is the most characteristic peripheral involvement in
pSS [48]. Sensory neuropathy is characterized clinically by
sensitive signs on the lemniscal way, with prevalence on the
lower limbs. Manifestations include distal paresthesias and
evidence of large-fiber sensory dysfunction on examination
and electrophysiological studies. In the series described by
Mellgren et al. [14], 33 pSS patients with neuropathy were
evaluated for neurological examinations, electromyography,
and nerve conduction studies. Evaluation also included sural
nerve biopsy in 11 patients. Thirty-two percent presented

Autoimmune Diseases
exclusive sensory neuropathy. Mori et al. [11] described
18 patients with painful sensory neuropathy and 36 with
sensory ataxic neuropathy from one series of 92 pSS with
neuropathy, confirming its high prevalence. This manifestation may be related to skin vasculitis but regularly is not
associated with other systemic manifestations of pSS.
4.1.2. Sensorimotor and Motor Polyneuropathy. A mixed sensorimotor polyneuropathy, involving large diameter fibers,
most commonly axonal, may be present in pSS. The
motor neuron involvement (amyotrophic lateral sclerosis
syndrome and anterior horn syndrome) is a rare neurological
manifestation in pSS [49] and may be associated with CNS
involvement [50].
Another manifestation is the acute motor axonal neuropathy (AMAN), a variant seen in nearly 5% of GuillainBarre syndrome. More than 60% of AMAN patients have
antibodies against ganglioside M1 (GM1) [51, 52]. One case
described by Awad et al. [53] showed a patient who developed rapidly fulminant AMAN with anti-GM1 antibodies.
Anti-SSA antibodies were also elevated, and sialadenitis
was evidenced by minor salivary gland biopsy. This patient
responded dramatically to intravenous immunoglobulin
(IVIg) treatment.
4.2. Sensory Ganglioneuronopathy. Sensory ganglioneuronopathy or sensory ataxic neuropathy produced by
posterior spinal roots involvement is manifested as sensory
ataxia, and it is characterized by severe impairment of
kinaesthetic sensation with no obvious motor involvement
[54]. This type of neuropathy may be considered as a
subgroup of sensory neuropathy. Physiopathology is
probably due to lymphocytic infiltrates on posterior roots
and spinal ganglions [11, 24, 54]. In these studies, it has
been described lymphocytic infiltrates without vasculitis
and degeneration of dorsal root ganglion neuronal cell
bodies. Some authors also propose a role of autoantibodies
in this manifestation. Among nine patients with pure
sensory neuropathy in the study by Delalande [15], four
presented clinical and electrophysiological features of
sensory ganglioneuronopathy with ataxia. This form
of neuropathy is chronic and progressive, occasionally
responding to treatment with IVIg [55].
4.3. Small-Fiber Neuropathy. Special mention requires the
more recent described small-fiber neuropathy in pSS. About
40% of pSS patients experience chronic neuropathic pain
with normal electrodiagnostic studies [5660]. In these
cases, quantification of epidermal nerve fiber density in
skin biopsy has been validated as a diagnostic tool of small
fiber neuropathy [61]. In the biopsy, the intraepidermal
nerve fiber density is calculated. In the article published by
Fauchais et al. [60], 14 pSSs with chronic neuropathic pain
and normal neurological examination were evaluated. Small
fiber neuropathy was confirmed by skin biopsy in 13/14
cases. Clinical manifestations were mainly distal burning
sensation, dysesthesia, prickling, and allodynia, localized in
both hands and feet.

Autoimmune Diseases
In the outpatient cohort described by Lopate et al.
[16], 50% of patients with pSS complained of painful distal
paresthesias with evidence of small-fiber sensory loss with
normal large-fiber function. Most part of these patients has
not been diagnosed before, showing that subclinical or mild
neuropathy may be present in pSS and can eventually lead to
disability.
The physiopathological mechanism is not well studied.
Ischemic and vasculitis processes have been implicated in the
small-fiber lesions [62]. Proinflammatory cytokines, such as
tumor necrosis alpha (TNF-), have been also implicated,
and some clinical improvement has seen with IVIg therapy
[63] and anti-TNF- [64] in other clinical conditions.
Some reports showed that patients who initially presented with a small-fiber neuropathy later developed a
sensory ataxic neuropathy [11], suggesting that small-fiber
neuropathy is on a continuum with large-fiber sensory
neuropathy.
4.4. Multiple Mononeuropathy. Similar to multiple mononeuropathy in the context of other AID, this complication
is rarely seen in pSS [9, 14]. In the series by Mori el al.
[11], 11 of 92 patients with pSS-associated neuropathy (12%)
were classified with multiple mononeuropathy. Their clinical
evolution is generally faster and more invaliding in pSS
compared to other diseases. This complication is associated with cutaneous vasculitis and cryoglobulinemia. The
multiple mononeuropathy is mainly produced by ischemic
mechanisms [65].
4.5. Trigeminal and Cranial Nerves Neuropathies. Often multiple and recurrent cranial nerves neuropathy may be present
in pSS. The most common is trigeminal neuropathy, followed by facial and oculomotor nerves involvement [66, 67].
This trigeminal neuropathy presents sensory rather motor
involvement. It involves generally the inferior branch of the
trigeminal nerve and remains usually clinically unilateral.
Tajima et al. [68] reported the prevalence of trigeminal
involvement as high as 50% of patients with cranial nerves
compromise. Mori et al. found that 15 of 92 patients (16%)
had trigeminal neuropathy with sensory impairment [11].
None presented motor trigeminal involvement. In Delalande
serie [15], coclear-vestibular nerve involvement seems to
be more frequent (35% of cranial nerve involvement) than
trigeminal neuropathy (29%).
4.6. Autonomic Neuropathy. In some patients, autonomic
neuropathy may be manifested with Adies pupils, anhidrosis,
fixed tachycardia, and orthostatic hypotension [9, 11, 16,
69]. Autonomic symptoms may be explained by both
ganglioneuronopathy and vasculitis. Mellgren et al. [14]
reported autonomic neuropathy in 6 of 33 patients with pSS
(18%). In the series by Andonopoulos et al. [70], autonomic
involvement was routinely searched in 32 patients with pSS.
Fifty percent of patients presented autonomic symptoms
induced by clinical tests. Most of cases have been reported to
be mild [71]. Mori et al. reported 3 of 92 patients with sever
autonomic neuropathy [11]. Adies pupil, associated with

5
autonomic involvement in pSS [72], is presumably caused
by neuronitis in the ciliary ganglion cells. Antibodies against
acetylcholine receptor have been described in patients with
pSS and autonomic symptoms [73].
However, other studies have not shown the increased
involvement of autonomic system compared to controls.
Niemela et al. [74] performed a complete evaluation of
autonomic functions on 30 pSS patients and 30 controls.
They showed no dierences between the two groups in any
of the test, concluding that the prevalence of autonomic
dysfunction in pSS is similar to general population.
4.7. Polyradiculoneuropathy. Acute of chronic polyradiculoneuropathies have been described in patients with pSS
[10, 11]. However, the prevalence in pSS seems to be similar
in the clinical, physiopathological, and anatomic context to
idiopathic polyradiculoneuropathies.

5. Diagnostic of Neurological
Involvement in pSS
5.1. Cerebrospinal Fluid. CSF may be useful to classify
some manifestations. Lymphocytes may be found in some
manifestations usually less of 50 cells/mm3 . In aseptic meningoencephalitis, CSF is abnormal with a higher number of
lymphocytes, increased level of proteins, and intrathecal
synthesis of gamma globulins [75]. The IgG index is
increased during periods of disease activity in up to 50% of
cases. CSF is also necessary to the dierential diagnosis (i.e.,
infection, multiple sclerosis). Oligoclonal bands (specifically
more than three bands) are highly specific of multiple
sclerosis diagnosis. These bands have been reported in about
20 to 25% of pSS compared to more than 90% in MS patients
[7678]. The oligoclonal bands are not stable during the
course of the pSS and can disappear after treatment with
steroids.
5.2. Magnetic Resonance Imaging. MRI abnormalities are
common in pSS and usually consist in hyperintense areas
in the subcortical and periventricular white matter on T2weighted and fluid-attenuated inversion recovery (FLAIR)
sequences [27, 28]. These lesions are usually less pronounced
in pSS than in patients with multiple sclerosis and rarely
touch the basal ganglia or the cerebral cortex.
5.3. Nerve Conduction Velocity Studies. Motor and sensory
nerve conduction velocity studies are tested in the median,
tibial, and sural nerve. These values give characteristic
patterns about the specific neuropathy, and they can differentiate the two major types: axonal degeneration and
demyelinating. Axonal polyneuropathy is the most frequent
pattern seen in pSS PNS involvement.
5.4. Electromyography. Electromyography patterns such as
action potential amplitude twice to normal and an increase
in duration of action potential may help to dierentiate the
neuropathies from myopathies. In pSS, electromyography
shows a typical pattern of axonal polyneuropathy, with

6
diminution of sensory amplitudes without latency or conduction velocity involvement. Asymptomatic neuropathies
can be found by systematic electromyography test [7].
5.5. Sural Nerve Biopsy. Most of the nerve studies in pSS
patients with neuropathy have been performed on sural
nerve. Mellgren et al. [14] reported vascular or perivascular
inflammation of small epineurial vessels in 11 patients with
pSS-related neuropathy. In two patients, a necrotizing vasculitis was diagnosed. In this study, axonal degeneration was
observed in both sensorimotor and sensory neuropathies.
In the study by Grin et al. [54], most of 12 biopsies
showed varying degrees of myelinated fiber loss. Six biopsies
had inflammatory infiltrates around epineurial vessels, but
necrotizing vasculitis was not evidenced. Cases of multiple
mononeuropathy have shown vasculitis in small arteries and
arterioles.
5.6. Skin Biopsy. Utility of skin biopsy in the diagnosis of
pSS-related neuropathy has been described in the section of
small-fiber neuropathy.
5.7. Neuromuscular Biopsy. The utility of neuromuscular biopsy in pSS-related neuropathy has been evaluated
[79]. In the study by Terrier et al., 40 pSS patients with
neuropathy underwent neuromuscular biopsy. Pathological
results (necrotizing vasculitis in 14 patients and lymphocytic
vasculitis in 8) were associated with acute-onset neuropathy,
multiple mononeuropathy, and sensorimotor involvement,
compared to 18 patients without vasculitis on the neuromuscular biopsy. Necrotizing vasculitis was significantly
associated with a better outcome and response to immunosuppressive treatment.
5.8. Autonomic Neuropathy Tests. To classify patients with
autonomic neuropathy, dierent test such as Till-table
test, gastrointestinal test, thermoregulatory sweat test, or
quantitative sudomotor axon reflex test may be used.

6. Biological Markers in Patients with pSS and

Neurological Manifestations
Anti-Ro and anti-La seem to be less frequent in pSS
patients with neurological involvement (40%) compared
to patients without neurological manifestations (60% of
positivity). Thus, new markers are necessary in pSS to
better classify subpopulations of patients with neurological involvement. Some antibodies have been described as
potential serological markers of neurological involvement
in pSS. However, their useful application is doubtful. IgA
and/or IgG anti-alpha-fodrin antibodies in pSS appear to be
common in neurological pSS (64.5% of 31 pSS patients with
neurological manifestations) [80]. However, this percentage
was not dierent from pSS patients without neurological
manifestations. Giordano et al. [81] evaluated IgM and IgG
anti-GM1 in 30 pSS patients and its relation with peripheral
neuropathy. Anti-GM1 antibodies were present in 12 patients
(6 with neuropathy and 6 without), thus showing little

Autoimmune Diseases
help to classify pSS patients with peripheral neuropathy.
Antineuronal antibodies have also been described in pSS
[82], although their pathological role is unknown.
Anti-GW182 antibodies directed against GW182 protein
(a protein located in cytoplasmic structures called GW
bodies) have been characterized in autoimmune diseases
(mainly in pSS) [83]. In this group, 18 sera of 200 patients
(9%) with autoimmune diseases were positive for antiGW182 antibodies. Interestingly, positive patients had mixed
motor and/or sensory neuropathy (n = 9), pSS with neurological symptoms (n = 3), and 6 patients presented SLE
or pSS without neurological manifestations. In conclusion,
anti-GW182 antibodies may help to classify patients with
autoimmune neurological involvement in dierent AID.
Of special interest, the antitype 3 muscarinic receptor
antibodies have been described in pSS. The IgA isotype may
be involved in the pathogenesis of autonomic dysfunction
and also may be useful as a novel marker in the pSS diagnosis
[84]. Their utility to discriminate patients with neurological
involvement has to be tested. Table 2 summarizes the antibodies in neurological manifestations in pSS patients.
Some other biological markers have been described in
neurological involvement in pSS. Among these markers,
patients with sensorimotor neuropathy have higher rates of
mixed cryoglobulin compared to pSS without neurological
manifestations (57% versus 11%), monoclonal gammapathy
(71% versus 17%), and NHL (57% versus 3%). On the
other hand, patients with sensory neuropathy show lower
prevalence of chronic B-cell activation markers (lower
prevalence of antinuclear antibodies, anti-SSA, and antiSSB) [85]. Therefore, these results demonstrate that the
pathophysiological mechanism is dierent according to
polyneuropathy type, and the B-cell activation markers can
be useful to classify a number of patients with a more severe
disease and risk of lymphoproliferation, accompanying some
neurological manifestations.

7. Treatment of Neurological Manifestations in

Sjogrens Syndrome
There is no consensus about the specific treatment of
neurological involvement in pSS. Generally, corticosteroid
therapy is initiated in patients with either CNS or PNS
[15, 86]. CNS involvement is usually treated with high
corticosteroid dose. In some cases, response to treatment
is exceptional. For example, Caselli et al. [87] showed one
patient with dementia who markedly improved after corticosteroid treatment. Concerning the treatment of acute and
chronic myelopathies, de Seze et al. [88] showed the tolerance
and clinical response of a combination regimen of steroids
and monthly cyclophosphamide. Fourteen patients (6 with
acute and 8 with chronic myelopathies) were evaluated.
Tolerance was good, and nine patients improved clinically
(including the total 6 patients with acute myelopathy), three
patients remained stable, and the other two patients presented moderate progression. Although randomized studies
are necessary, this treatment needs to be considered in
patients with progressive disease.

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7
Table 2: Antibodies in neurological manifestations of primary Sjogrens syndrome.

Antibody

Clinical association

Reference

Anti-SSA and anti-SSB

Most of studies show lower prevalence of anti-SSA and

anti-SSB antibodies in pSS with neurological
involvement. In one series, patients with nonataxic
sensory neuropathy had lower prevalence of anti-SSA
(40% versus 72%) and anti-SSB (15% versus 41%).

Sene et al. [85]

Anti-SSA

This paper showed that anti-Ro antibodies were

positive in 48% of patients with CNS compared to only
24% of all patients with pSS. However, the anti-SSA
antibodies were detected by double immunodiusion
and not by ELISA.

Alexander et al. [18]

Anti-alpha fodrin (IgA and IgG)

These antibodies are common patients in pSS.

However, there are not dierences between patients
with or without clinical neurological involvement.

De Seze et al. [88]

Anti-GM1 (IgM and IgG)

No dierences between pSS patients with or without

neurological involvement.

Giordano et al. [81]

Antineuronal antibodies

In a large series of patients with neurological disorders

(n = 882), these antibodies were detected in patients
with pSS and neurological involvement, although the
specificity has to be defined. Antiganglion neuron
antibodies have been also reported.

Murata et al. [25],

Vianello et al. [82]

Anti-GW182

Detected in patients with mixed motor and/or sensory

neuropathy without pSS and also in neurological
involvement in pSS patients.

Eystathioy et al. [83]

GM1: ganglioside; GW182: protein located in cytoplasmic structures called GW bodies; CNS: central nervous system; pSS: primary Sjogren syndrome.

Classically, peripheral neuropathy in patients with pSS

responds poorly to treatment [11, 15, 86]. Some groups
recommend only treating the symptoms according to the
severity. In other patients, immunosuppressive therapy based
on corticosteroids, cyclophosphamide, azathioprine, and
even plasmapheresis has shown only mild success [8991].
In the series reported by Terrier et al. [79], patients with
necrotizing vasculitis have a better response to immunosuppressive treatment, mainly with cyclophosphamide (71% of
patients with necrotizing vasculitis showed good response
compared to 25% of patients with lymphocytic vasculitis).
Grin et al. reported a treatment based on corticosteroids
and associated in some cases with azathioprine, intravenous
cyclophosphamide or plasma exchanges [54]. Only one
patient with a relapsing course responded to corticosteroid
treatment. Mori et al. suggested that corticosteroids are
suitable for multiple neuropathy and multiple cranial neuropathy [11].
IVIg has been also reported as a good therapeutic option
in some painful sensory neuropathy cases [92] and in
radiculoneuropathy. In a recently series of 19 pSS patients
with peripheral neuropathy, intravenous immunoglobulin
treatment was evaluated [93]. In this study, 8 patients
(42%) showed a decrease of the disability Modified Rankin
Scale, corresponding to a clinical improvement. Patients
with sensorimotor or nonataxic sensory neuropathy were
markedly improved compared to patients with ataxic neuropathy (2/9). The authors concluded that clinical benefits of IVIg treatment depend on the specific clinical
subtype.

Caroyer et al. [94] showed improvement in sensory

ganglioneuronopathy treated with infliximab. However, no
controlled trials have shown ecacy of infliximab or others
anti-TNF in pSS-related neuropathy.
Rituximab, an anti-CD20 antibody, may be useful in
systemic complications in pSS patients [95, 96] and in
some cases of refractory neuropathy. Recently, Mekinian
et al. [97] reported 17 patients with pSS and PNS involvement treated with rituximab. Neurological improvement
was observed in 11/17 patients (65%) at three months.
Best results were observed in patients with cryoglobulinemia or vasculitis-related PNS involvement (9/10 patients
improved).
The benefits from treatment with oromucosal IFN-
in pSS have been reported by several groups [98101].
Due to possible eects on sicca symptoms, Yamada et al.
[102] reported three cases of pSS-associated neuropathy
treated with oral IFN- (two patients with sensory ataxic
neuronopathy and one patient with axonal sensorimotor
neuropathy with demyelinating features). All three patients
responded well to IFN-, improving the neurological symptoms. Sicca symptoms, antibodies titres, and focus score
of salivary gland biopsy were also improved. However, the
mechanisms whereby IFN- induces neurological improvement in pSS are uncertain.
In conclusion, neurological manifestations are common
in pSS and often precede the diagnosis. The accurate prevalence of these manifestations is dicult to assess, because
the heterogeneity of the series. The pathogenic mechanisms
responsible for most forms of neurological involvement in

8
pSS remain unknown, but vascular, ischemic, and immunological mechanisms have been described. Controlled and
population-based trials are necessary to better characterize
the neurological manifestations in pSS and their therapeutic
response.

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